X-ray crystallography (crystallography) is an established, well-studied technique that provides what can be best described as a three-dimensional picture of what a molecule looks like in a crystal. Scientists have used crystallography to solve the crystal structures for many biologically important molecules. Many classes of biomolecules can be studied by crystallography, including, but not limited to, proteins, DNA, RNA and viruses. Scientists have even reported the crystal structures of biomolecules that carry ligands within its receptors (a "ligand-receptor complex").
Given a "picture" of a target biomolecule or a ligand-receptor complex, scientists can look for pockets or receptors where biological activity can take place. Then scientists can experimentally or computationally design high-affinity ligands (or drugs) for the receptors. Computational methods have alternatively been used to screen for the binding of small molecules. However, these previous attempts have met with limited success. Several problems plague ligand design by computational methods. Computational methods are based on estimates rather than exact determinations of the binding energies, and rely on simple calculations when compared with the complex interactions that exist within a biomolecule. Moreover, computational models require experimental confirmation which often expose the models as false positives that do not work on the real target.
Moreover, experimental high-affinity ligand design based on a "picture" of the ligand-receptor complex has been limited to biomolecules that already have known ligands. Finally, scientists only recently reported the crystallographic study of interactions between organic solvents and target biomolecules. Allen et al., J. Phys. Chem., v. 100, pp. 2605-11 (1996). However, these studies are limited to mapping solvent sites rather than ligand sites. It would be desirable to directly identify potential ligands, and to obtain detailed information on how the ligand binds and changes in the target biomolecule. In addition, methods for identifying and/or designing ligands which possess biological and/or pharmaceutical activity with respect to a given target molecule would be desireable.